Importance of conformational loop in vasopressin analogs for the interaction with V2 vasopressin receptor and the effect on antitumoral activity

IANNUCCI, NANCY BEATRIZ; RIPOLL, GISELLA V.; GARONA, J.; CASCONE, OSVALDO; GÓMEZ, DANIEL E.; ALONSO, DANIEL F.

San Miguel de Tucumán, Argentina

Congreso; XLV Reunión Anual de SAIB; 2009

SAIB

Desmopressin (DDAVP) is a vasopressin (VP) analogue with antitumoral activity in preclinical model and canine protocols. This cyclic nonapeptide was punctually substituted in positions 4 and 5 in order to improve its biological activity and half life. These positions are included in the loop formed between the disulphide bridge of the molecule. We suspected that the loop is strongly related to the interaction of desmopressin and its analogs with the V2 receptor in endothelial and some tumor cells. In order to demonstrate this hypothesis we analyzed the biological activity of the loop tetrapeptides (fragment 2-5) of DDAVP and two analogs (VQ and AQ) and compared them with the lead molecules. Because the expression of V2 vasopressin receptor has been associated with antiproliferative behavior we have analyzed the peptides abilities to modify in vitro cell proliferation of mammary carcinoma cells MCF7 expressing V2 receptor. The incubation with VQ analog (100-1500 nM) during 72 h significantly reduced cell proliferation (p<0.001) showing a better performance than DDAVP and AQ analogue in doses of 500-1500 nM (p<0.05). Fragments 2-5 showed lower biological activity by means of its ability to reduce cell proliferation in low concentrations (100-500 nM) and the effect was completely abolished in higher concentrations. The results could indicate that loop conformation by disulphide bridge formation is essential for the biological activity of the molecule.